Novel compounds

ABSTRACT

The invention relates to substituted phenoxyacetic acids (I) as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.

The present invention relates to substituted phenoxyacetic acids asuseful pharmaceutical compounds for treating respiratory disorders,pharmaceutical compositions containing them, and processes for theirpreparation.

EPA 1 170 594 discloses methods for the identification of compoundsuseful for the treatment of disease states mediated by prostaglandin D2,a ligand for orphan receptor CRTH2. GB 1356834 discloses a series ofcompounds said to possess anti-inflammatory, analgesic and antipyreticactivity. It has been found that certain phenoxyacetic acids are activeat the CRTH2 receptor, and as a consequence are expected to bepotentially useful for the treatment of various respiratory diseases,including asthma and COPD.

In a first aspect the invention therefore provides a compound of formula(I) or a pharmaceutically acceptable salt or solvate thereof:

in whichX is C₁₋₆alkyl, OR⁶ or OR¹⁷Y is selected from hydrogen, halogen, CN, nitro, SO₂R³, OR⁴, SR⁴, SOR³,SO₂NR⁴R⁵, CONR⁴R⁵, NR⁴R⁵, NR⁶SO₂R³, NR⁶CO₂R⁶, NR⁶COR³, C₂-C₆alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl or C₁₋₆alkyl, the latter four groupsbeing optionally substituted by one or more substituents independentlyselected from halogen, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶ where n is 0, 1 or 2;Z is aryl or a ring A, where A is a six membered heterocyclic aromaticring containing one or more nitrogen atoms or may be a 6,6 or 6,5 fusedbicycle containing one or more O, N, S atoms, the aryl or A rings allbeing optionally substituted by one or more substituents independentlyselected from from hydrogen, halogen, CN, OH, SH, nitro, COR⁹, CO₂R⁶,SO₂R⁹, OR⁹, SR⁹, SOR⁹, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹, NHSO₂R⁹,NR⁹SO₂R⁹, NR⁶CO₂R⁶, NHCOR⁹, NR⁹COR⁹, NR⁶CONR⁴R⁵, NR⁶SO₂NR⁴R⁵, aryl,heteroaryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl or C₁₋₆alkyl,the latter four groups being optionally substituted by one or moresubstituents independently selected from halogen, C₃-C₇ cycloalkyl, OR⁶,NR⁶R⁷, S(O)_(n)R⁶ (where n is 0, 1 or 2), CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷ andNR⁶SO₂R⁷;R¹ and R² independently represent a hydrogen atom, halogen, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl or a C₁₋₆alkyl group, thelatter four groups being optionally substituted by one or moresubstituents independently selected from halogen, C₃-C₇ cycloalkyl,NR⁶R⁷, OR⁶, S(O)_(n)R⁶ (where n is 0, 1 or 2);orR¹ and R² together can form a 3-8 membered ring optionally containingone or more atoms selected from O, S, NR⁶ and itself optionallysubstituted by one or more C₁-C₃ alkyl or halogen;R³ represents C₃-C₇ cycloalkyl or C₁₋₆alkyl which may be optionallysubstituted by one or more substituents independently selected fromhalogen, C₃-C₇ cycloalkyl, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶ (where n=0, 1 or2), CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷ and NR⁶SO₂R⁷;R⁴ and R⁵ independently represent hydrogen, C₃-C₇ cycloalkyl orC₁₋₆alkyl, the latter two groups being optionally substituted by one ormore substituents independently selected from halogen, C₃-C₇ cycloalkyl,OR⁶ and NR⁶R⁷, S(O)_(n)R⁶ (where n=0, 1 or 2), CONR⁶R⁷, NR⁶COR⁷,SO₂NR⁶R⁷ and NR⁶SO₂R⁷;orR⁴ and R⁵ together with the nitrogen atom to which they are attached canform a 3-8 membered saturated heterocylic ring optionally containing oneor more atoms selected from O, S(O)_(n) (where n=0, 1 or 2), NR⁸, anditself optionally substituted by halogen or C₁₋₃ alkyl;R⁶ and R⁷ independently represents a hydrogen atom or C₁-C₆ alkyl;R⁸ is hydrogen, C₁₋₄ alkyl, —COC₁-C₄ alkyl, CO₂C₁-C₄alkyl orCONR⁶C₁-C₄alkyl;R⁹ represents aryl, heteroaryl, C₃-C₇ cycloalkyl or C₁₋₆alkyl, thelatter two groups may be optionally substituted by one or moresubstituents independently selected from halogen, C₃-C₇ cycloalkyl,aryl, heteroaryl OR⁶ and NR⁶R⁷, S(O)_(n)R⁶ (where n=0, 1 or 2), CONR⁶R⁷,NR⁶COR⁷, SO₂NR⁶R⁷ and NR⁶SO₂R⁷;R¹⁰ and R¹¹ independently represent aryl or heteroaryl, hydrogen, C₃-C₇cycloalkyl or C₁₋₆alkyl, the latter two groups being optionallysubstituted by one or more substituents independently selected fromhalogen, C₃-C₇ cycloalkyl, aryl, heteroaryl, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶(where n=0, 1 or 2), CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷ and NR⁶SO₂R⁷;orR¹⁰ and R¹¹ together with the nitrogen atom to which they are attachedcan form a 3-8 membered saturated heterocylic ring optionally containingone or more atoms selected from O, S(O)_(n) (where n=0, 1 or 2), NR⁸,and itself optionally substituted by halogen or C₁-C₃ alkyl.R¹⁷ is C₁₋₆ alkyl which is substituted by one or more halogen atoms;

Examples of aryl include phenyl and naphthyl.

Heteroaryl is defined as a 5-7 member aromatic ring or can be 6,6- or6,5-fused bicyclic ring optionally containing one or more heteroatomsselected from N; S or O. The bicyclic ring may be linked through carbonor nitrogen and may be attached through the 5 or 6 membered ring and canbe fully or partially saturated.

Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole,imidazole, furan, isoxazole, pyrrole, isothiazole and azulene, naphthyl,indene, quinoline, isoquinoline, indole, indolizine, benzo[b]furan,benzo[b]thiophene, 1H-indazole, benzimidazole, benzthiazole,benzoxazole, purine, 4H-quinolizine, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinolone and1,2-methylenedioxy benzene.

Aryl or heteroaryl groups can be optionally substituted by one or moresubstituents independently selected from from hydrogen, halogen, CN, OH,SH, nitro, CO₂R⁶, SO₂R⁹, OR⁹, SR⁹, SOR⁹, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR¹⁰R¹¹,NHSO₂R⁹, NR⁹SO₂R⁹, NR⁶CO₂R⁶, NHCOR⁹, NR⁹COR⁹, aryl, heteroaryl, C₂-C₆alkenyl, C₂-C₆ alkyl, C₃-C₇ cycloalkyl or C₁₋₆alkyl, the latter fourgroups being optionally substituted by one or more substituentsindependently selected from halogen, C₃-C₇ cycloalkyl, OR⁶, NR⁶R⁷,S(O)_(n)R⁶ (where n is 0, 1 or 2), CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷ andNR⁶SO₂R⁷.

The group A is a six membered heterocyclic ring containing one or morenitrogen atoms or may be a 6,6 or 6,5 fused bicycle containing one ormore O, N, S atoms. Examples of suitable rings include pyridine,pyrimidine, pyrazine, pyridazine, indole, quinoline, isoquinoline,benzimidazole, benzthiazole, benzofuran, benzoxazole, benzthiophene,phthalazine and quinazoline.

In the context of the present specification, unless otherwise indicated,an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituentgroup may be linear or branched.

Heterocyclic rings as defined for R⁴, R⁵ and R¹⁰, R¹¹ means saturatedheterocycles, examples include morpholine, azetidine, pyrrolidine,piperidine and piperazine. Substuitents can be present on carbon orappropriate nitrogen atoms of said rings.

Preferably X is C₁₋₄alkyl or C₁₋₄alkoxy, more-preferably methyl, ethylor methoxy.

Preferably Y is hydrogen.

Preferably Z is phenyl optionally substituted as defined above. One ormore substitents can be present. Preferred substituents for all Z groupsinclude those substituents exemplified herein, in particular halogen,C₁₋₃alkyl, cyano and SO₂R⁹. Most preferably Z is phenyl or phenylsubstituted by a single substituent selected from SO₂Me, SO₂Et or CN ordi-substituted by SO₂Et and methyl.

Preferably R¹ and R² are independently hydrogen or C₁₋₃ alkyl. Morepreferably R¹ and R² are both hydrogen or one is hydrogen and the otheris methyl.

Preferred compounds of the invention include:

-   [(5-Methylbiphenyl-2-yl)oxy]acetic acid,-   {[5-Ethyl-4′-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid-   {[4′-(Ethylsulfonyl)-5-methoxybiphenyl-2-yl]oxy}acetic acid-   [[4-Chloro-4′-(ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-acetic    acid-   [[4′-(Ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-acetic    acid-   2-[[3′-Cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid-   2-[[2′-Fluoro-5′-cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic    acid    and pharmaceutically acceptable salts and solvates thereof.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The compound of formula (I) above may be converted to a pharmaceuticallyacceptable salt or solvate thereof, preferably a basic addition saltsuch as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc,benzathine, chloroprocaine, choline, diethanolamine, ethanolamine,ethyldiamine, meglumine, tromethamine or procaine, or an acid additionsalt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-toluenesulphonate.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups in the startingreagents or intermediate compound may need to be protected by protectinggroups. Thus, the preparation of the compound of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups. The protection and deprotection of functional groups is fullydescribed in ‘Protective Groups in Organic Chemistry’, edited by J. W.F. McOmie, Plenum Press (1973), and ‘Protective Groups in OrganicSynthesis’, 3rd edition, T. W. Greene & P. G. M. Wuts,Wiley-Interscience (1999).

Compounds of formula (I) can be prepared by reaction of a compound offormula (II):

in which X, Y and Z are as defined in formula (I) or are protectedderivatives thereof; with a compound of formula (III):L-CR¹R²CO₂R¹²  (III)

Where R¹ and R² are as defined in formula (I) or are protectedderivatives thereof, R¹² is H or C₁-C₁₀ alkyl group and L is a leavinggroup, and optionally thereafter in any order:

removing any protecting group

hydrolysing the ester group R¹² to the corresponding acid

oxidation of sulphides to sulphoxides or sulphones

forming a pharmaceutically acceptable salt or solvate.

The reaction can be carried out in a suitable solvent such as DMF usinga base such as potassium carbonate or the like. Suitable groups R¹²include C₁₋₆ alkyl groups such as methyl, ethyl or tert-butyl. SuitableL is a leaving group such as halo, in particular chlorine or bromine. Lmay also be hydroxy so that a Mitsunobu reaction may be performed withcompound (II) using for example triphenylphosphine and diethylazodicarboxylate.

Hydrolysis of the ester group R¹² can be carried out using routineprocedures, for example treatment of methyl and ethyl esters withaqueous sodium hydroxide, and treatment of tert-butyl esters with acidssuch as trifluoroacetic acid.

Compounds of formula (II) can be prepared by reaction of a compound offormula (IV) with a compound of formula (V) via a Suzuki couplingreaction followed by deprotection of R¹³ when R¹³ is not equal to H:

in which X, Y and Z are as defined in formula (I) or are protectedderivatives thereof, R¹³ is H or a suitable protecting group, forexample benzyl, L¹ is iodide, bromide, chloride or triflate and R¹⁴ andR¹⁵ are H or C₁-C₆ alkyl groups or R¹⁴ and R¹⁵ together can form a 5 or6 membered ring optionally substituted by one or more C₁-C₃ alkyl.

The reaction can be carried out in a suitable solvent such as dioxaneusing a palladium catalyst such as[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium and a base suchas cesium fluoride, preferably at elevated temperatures.

Compounds of formula (IV) can be prepared from a compound of formula(VI) by formation of an organometallic (VII) followed by reaction with aborate ester, as outlined in Scheme I.

in which X, Y are as defined in formula (I) or are protected derivativesthereof, R¹³ is as defined in formula (IV), E is hydrogen or halogen andM is a metal such as Na or Li. For example when R¹³ is benzyl and E isbromine, butyl lithium can be used to form the intermediate (VII) whereM=Li. The reaction is performed at −78° C. in diethylether, thenquenched with a borate ester such as trimethylborate.

Compounds of formula (IV) may also be prepared by a palladium catalysedcoupling of compounds of formula (VII) with a suitable boronic ester,for example (IX) or (X).

in which X, Y and R¹³ are as defined above and G is halogen or triflate

Compounds of formula (II) may also be prepared by reaction of a compoundof formula (XI) with a compound of formula (XII) using Suzuki couplingmethodology.

in which X, Y, Z, R¹³, L¹, R¹⁴ and R¹⁵ are as defined above andcompounds of formula (XI) and (XII) can be made using the samemethodology as above.

Compounds of formula (II), where Z=heteroaryl may also be prepared byring synthesis, for example a compound of formula (XIII) may be formedby reaction of a compound of, formula (XIV) with a compound of formula(XV).

X, Y and R¹³ are as defined above and R¹⁶ is as defined as a substituenton Z as defined in formula (I) or are protected derivatives thereof. Thereaction can be carried out in a solvent such as ethanol under reflux,and a base such as sodium ethoxide can be used if compound of formula(XV) is a salt

When R¹⁶ is a group S-alkyl, this may be further elaborated by oxidationto the sulfoxide or sulphone using an oxidizing agent such as mcpba inDCM at RT. This may then be displaced with an appropriate nucleophile asdefined for Z in formula 1. Scheme 2;

The sequence of the steps above may be changed, for example a compoundof formula (XVI) may be formed by the reaction of a compound of formula(XVII) with a compound of formula (XII) using a Suzuki coupling.

Compounds of formula (I) may also be prepared by reaction of a compoundof formula (XVIII) in which in which X, Y, R¹, R², R¹², R¹⁴ and R¹⁵ areas defined above with a compound of formula (V) using Suzuki couplingmethod as defined above.

A compound of formula (XVIII) may be prepared by method A or B

The acid was first converted to the acid chloride, using for exampleoxalylchloride in DCM at RT, then reacted with3-methyl-3-oxetanemethanol in the presence of a base such astriethylamine to give the ester. The oxetane ester is the rearranged tothe OBO ester using boron trifluoride diethyletherate in DCM at −78° C.to RT. Deprotonation with a base such as sec-butyl lithium at lowtemperature followed by quenching with trimethylborate gave theprotected diacid which was then deprotected using HCl then sodiumhydroxide

A compound of formula (IV) where R¹³=Bn and R¹⁴ and R¹⁵═H and pinacolcan bestirred at RT in a suitable solvent such as diethylether to givethe boronate ester. The benzyl group may be removed by hydrogenation atRT using palladium on carbon as catalyst then alkylated with a compoundof formula (III) using a base or mitsunobu conditions. Treatment withacid such as HCl or trifluoroacetic acid then removes the protectinggroups.

In a further aspect, the present invention provides the use of acompound of formula (I), a prodrug, pharmaceutically acceptable salt orsolvate thereof for use in therapy.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of CRTh2 receptor activity, and may be used inthe treatment (therapeutic or prophylactic) of conditions/diseases inhuman and non-human animals which are exacerbated or caused by excessiveor unregulated production of PGD₂ and its metabolites. Examples of suchconditions/diseases include:

-   -   (1) (the respiratory tract) obstructive airways diseases        including: asthma (such as bronchial, allergic, intrinsic,        extrinsic and dust asthma particularly chronic or inveterate        asthma (e.g. late asthma and airways hyper-responsiveness));        chronic obstructive pulmonary disease (COPD)(such as        irreversible COPD); bronchitis (including eosinophilic        bronchitis); acute, allergic, atrophic rhinitis or chronic        rhinitis (such as rhinitis caseosa, hypertrophic rhinitis,        rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa,        membranous rhinitis (including croupous, fibrinous and        pseudomembranous rhinitis), scrofoulous rhinitis, perennial        allergic rhinitis, easonal rhinitis (including rhinitis nervosa        (hay fever) and vasomotor rhinitis); nasal polyposis;        sarcoidosis; farmer's lung and related diseases; fibroid lung;        idiopathic interstitial pneumonia; cystic fibrosis; antitussive        activity; treatment of chronic cough associated with        inflammation or iatrogenic induced;    -   (2) (bone and joints) arthrides including rheumatic, infectious,        autoimmune, seronegative, spondyloarthropathies (such as        ankylosing spondylitis, psoriatic arthritis and Reiter's        disease), Behcet's disease, Sjogren's syndrome and systemic        sclerosis;    -   (3) (skin and eyes) psoriasis, atopical dermatitis, contact        dermatitis, other eczmatous dermitides, seborrhoetic dermatitis,        Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis        bullosa, urticaria, angiodermas, vasculitides, erythemas,        cutaneous eosinophilias, chronic skin ulcers, uveitis, Alopecia        greatacorneal ulcer and vernal conjunctivitis;    -   (4) (gastrointestinal tract) Coeliac disease, proctitis,        eosinopilic gastro-enteritis, mastocytosis, Crohn's disease,        ulcerative colitis, irritable bowel disease; food-related        allergies which have effects remote from the gut, (such as        migraine, rhinitis and eczema);    -   (5) (central and peripheral nervous system) Neurodegenerative        diseases and dementia disorders (such as Alzheimer's disease,        amyotrophic lateral sclerosis and other motor neuron diseases,        Creutzfeldt-Jacob's disease and other prion diseases, HIV        encephalopathy (AIDS dementia complex), Huntington's disease,        frontotemporal dementia, Lewy body dementia and vascular        dementia), polyneuropathies (such as Guillain-Barré syndrome,        chronic inflammatory demyelinating polyradiculoneuropathy,        multifocal motor neuropathy), plexopathies, CNS demyelination        (such as multiple sclerosis, acute disseminated/haemorrhagic        encephalomyelitis, and subacute sclerosing panencephalitis),        neuromuscular disorders (such as myasthenia gravis and        Lambert-Eaton syndrome), spinal diorders (such as tropical        spastic paraparesis, and stiff-man syndrome), paraneoplastic        syndromes (such as cerebellar degeneration and        encephalomyelitis), CNS trauma, migraine and stroke.    -   (6) (other tissues and systemic disease) atherosclerosis,        acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus;        systemic lupus, erythematosus; Hashimoto's thyroiditis, type I        diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE        syndrome, lepromatous leprosy, idiopathic thrombocytopenia        pupura; post-operative adhesions, sepsis and        ischemic/reperfusion injury in the heart, brain, peripheral        limbs hepatitis (alcoholic, steatohepatitis and chronic viral),        glomerulonephritis, renal impairment, chronic renal failure and        other organs    -   (7) (allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin and cornea; and chronic graft versus host disease;    -   (8) Diseases associated with raised levels of PGD₂ or its        metabolites.    -   (1) (respiratory tract)—obstructive diseases of the airways        including: asthma, including bronchial, allergic, intrinsic,        extrinsic, exercise-induced, drug-induced (including aspirin and        NSAID-induced) and dust-induced asthma, both intermittent and        persistent and of all severities, and other causes of airway        hyper-responsiveness; chronic obstructive pulmonary disease        (COPD); bronchitis, including infectious and eosinophilic        bronchitis; emphysema; bronchiectasis; cystic fibrosis;        sarcoidosis; farmer's lung and related diseases;        hypersensitivity pneumonitis; lung fibrosis, including        cryptogenic fibrosing alveolitis, idiopathic interstitial        pneumonias, fibrosis complicating anti-neoplastic therapy and        chronic infection, including tuberculosis and aspergillosis and        other fungal infections; complications of lung transplantation;        vasculitic and thrombotic disorders of the lung vasculature, and        pulmonary hypertension; antitussive activity including treatment        of chronic cough associated with inflammatory and secretory        conditions of the airways, and iatrogenic cough; acute and        chronic rhinitis including rhinitis medicamentosa, and vasomotor        rhinitis; perennial and seasonal allergic rhinitis including        rhinitis nervosa (hay fever); nasal polyposis; acute viral        infection including the common cold, and infection due to        respiratory syncytial virus, influenza, coronavirus (including        SARS) and adenovirus.    -   (2) (bone and joints) arthritides associated with or including        osteoarthritis/osteoarthrosis, both primary and secondary to        e.g. congenital hip dysplasia; cervical and lumbar spondylitis,        and low back and neck pain; rheumatoid arthritis and Still's        disease; seronegative spondyloarthropathies including ankylosing        spondylitis, psoriatic arthritis, reactive arthritis and        undifferentiated spondarthropathy; septic arthritis and other        infection-related arthopathies and bone disorders such as        tuberculosis, including Potts' disease and Poncet's syndrome;        acute and chronic crystal-induced synovitis including urate        gout, calcium pyrophosphate deposition disease, and calcium        apatite related tendon, bursal and synovial inflammation;        Behcet's disease; primary and secondary Sjogren's syndrome;        systemic sclerosis and limited scleroderma; systemic lupus        erythematosus, mixed connective tissue disease, and        undifferentiated connective tissue disease; inflammatory        myopathies including dermatomyositits and polymyositis;        polymalgia rheumatica; juvenile arthritis including idiopathic        inflammatory arthritides of whatever joint distribution and        associated syndromes, and rheumatic fever and its systemic        complications; vasculitides including giant cell arteritis,        Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis        nodosa, microscopic polyarteritis, and vasculitides associated        with viral infection, hypersensitivity reactions, cryoglobulins,        and paraproteins; low back pain; Familial Mediterranean fever,        Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi        disease; drug-induced arthalgias, tendonititides, and        myopathies.    -   (3) (skin) psoriasis, atopic dermatitis, contact dermatitis or        other eczematous dermatoses, and delayed-type hypersensitivity        reactions; phyto- and photodermatitis; seborrhoeic dermatitis,        dermatitis herpetiformis, lichen planus, lichen sclerosus et        atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus        erythematosus, pemphigus, ipemphigoid, epidermolysis bullosa,        urticaria, angioedema, vasculitides, toxic erythemas, cutaneous        eosinophilias, alopecia areata, male-pattern baldness, Sweet's        syndrome, Weber-Christian syndrome, erythema multiforme;        cellulitis, both infective and non-infective; panniculitis;        cutaneous lymphomas, non-melanoma skin cancer and other        dysplastic lesions; drug-induced disorders including fixed drug        eruptions.    -   (4) (eyes) blepharitis; conjunctivitis, including perennial and        vernal allergic conjunctivitis; iritis; anterior and posterior        uveitis; choroiditis; autoimmune; degenerative or inflammatory        disorders affecting the retina; ophthalmitis including        sympathetic ophthalmitis; sarcoidosis; infections including        viral, fungal, and bacterial.    -   (5) (gastrointestinal tract) glossitis, gingivitis,        periodontitis; oesophagitis, including reflux; eosinophilic        gastro-enteritis, mastocytosis, Crohn's disease, colitis        including ulcerative colitis, proctitis, pruritis ani; coeliac        disease, irritable bowel syndrome, and food-related allergies        which may have effects remote from the gut (for example        migraine, rhinitis or eczema).    -   (6) (abdominal) hepatitis, including autoimmune, alcoholic and        viral; fibrosis and cirrhosis of the liver; cholecystitis;        pancreatitis, both acute and chronic.    -   (7) (genitourinary) nephritis including interstitial and        glomerulonephritis; nephrotic syndrome; cystitis including acute        and chronic (interstitial) cystitis and Hunner's ulcer; acute        and chronic urethritis, prostatitis, epididymitis, oophoritis        and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile        dysfunction (both male and female).    -   (8) (Allograft rejection) acute and chronic following, for        example, transplantation of kidney, heart, liver, lung, bone        marrow, skin or cornea or following blood transfusion; or        chronic graft versus host disease;    -   (9) (CNS) Alzheimer's disease and other dementing disorders        including CJD and nvCJD; amyloidosis; multiple sclerosis and        other demyelinating syndromes; cerebral atherosclerosis and        vasculitis; temporal arteritis; myasthenia gravis; acute and        chronic pain (acute, intermittent or persistent, whether of        central or peripheral origin) including visceral pain, headache,        migraine; trigeminal neuralgia, atypical facial pain, joint and        bone pain, pain arising from cancer and tumor invasion,        neuropathic pain syndromes including diabetic, post-herpetic,        and HIV-associated neuropathies; neurosarcoidosis; central and        peripheral nervous system complications of malignant, infectious        or autoimmune processes.    -   (10) Other auto-immune and allergic disorders including        Hashimoto's thyroiditis, Graves' disease, Addison's disease,        diabetes mellitus, idiopathic thrombocytopaenic purpura,        eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid        syndrome.    -   (11) Other disorders with an inflammatory or immunological        component; including acquired immune deficiency syndrome (AIDS),        leprosy, Sezary syndrome, and paraneoplastic syndromes.    -   (12) (Cardiovascular); atherosclerosis, affecting the coronary        and peripheral circulation; pericarditis; myocarditis,        inflammatory and auto-immune cardiomyopathies including        myocardial sarcoid; ischaemic reperfusion injuries;        endocarditis, valvulitis, and aortitis including infective (e.g.        syphilitic); vasculitides; disorders of the proximal and        peripheral veins including phlebitis and thrombosis, including        deep vein thrombosis and complications of varicose veins.    -   (13) (Oncology) treatment of common cancers including prostate,        breast, lung, ovarian, pancreatic, bowel and colon, stomach,        skin and brain tumors and malignancies affecting the bone marrow        (including the leukaemias) and lymphoproliferative systems, such        as Hodgkin's and non-Hodgkin's lymphoma; including the        prevention and treatment of metastatic disease and tumour        recurrences, and paraneoplastic syndromes.    -   (14) Diseases associated with raised levels of PGD₂ or its        metabolites.

Thus, the present invention provides a compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

Preferably the compounds of the invention are used to treat diseases inwhich the chemokine receptor belongs to the CRTh2 receptor subfamily.

Particular conditions which can be treated with the compounds of theinvention are asthma, rhinitis and other diseases in which raised levelsof PGD₂ or its metabolites. It is preferred that the compounds of theinvention are used to treat asthma.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy, in particular for a disease mediated.

In a further aspect, the present invention provides the use of acompound or formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy in combination with drugs used to treatasthma and rhinitis (such as inhaled and oral steroids, inhaledβ2-receptor agonists and oral leukotriene receptor antagonists).

The invention further relates to combination therapies wherein acompound of formula (I) or a pharmaceutically acceptable salt, solvateor in vivo hydrolysable ester thereof, or a pharmaceutical compositionor formulation comprising a compound of formula (I) is administeredconcurrently or sequentially or as a combined preparation with anothertherapeutic agent or agents, for the treatment of one or more of theconditions listed.

In particular, for the treatment of the inflammatory diseases rheumatoidarthritis, psoriasis, inflammatory bowel disease, COPD, asthma andallergic rhinitis the compounds of the invention may be combined withagents such as tumour necrosis factor alpha (TNF-α) inhibitors such asanti-TNF monoclonal antibodies (for example Remicade, CDP-870 andadalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel);non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitors whether appliedtopically or systemically (such as piroxicam, diclofenac, propionicacids such as naproxen, flubiprofen, fenoprofen, ketoprofen andibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,azapropazone, pyrazolones such as phenylbutazone, salicylates such asaspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib,valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids(whether administered by topical, oral, intramuscular, intravenous, orintra-articular routes); methotrexate, lefunomide; hydroxychloroquine,d-penicillamine, auranofin or other parenteral or oral goldpreparations.

The present invention still further relates to the combination of acompound of the invention together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to the combination of acompound of the invention together with a receptor antagonist forleukotrienes (LT)B4, LTC4, LTD4, and LTE4. selected from the groupconsisting of the phenothiazin-3-1s such as L-651,392; amidino compoundssuch as CGS-25019c; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention together with a phosphodiesterase (PDE)inhibitor such as the methylxanthanines including theophylline andaminophylline; and selective PDE isoenzyme inhibitors including PDE4inhibitors and inhibitors of the isoform PDE4D, and inhibitors of PDE5.

The present invention still further relates to the combination of acompound of the invention together with histamine type 1 receptorantagonists such as cetirizine, loratadine, desloratadine, fexofenadine,acrivastine, terfenadine, astemizole, azelastine, levocabastine,chlorpheniramine, promethazine, cyclizine, and mizolastine appliedorally, topically or parenterally.

The present invention still further relates to the combination of acompound of the invention together with a gastroprotective histaminetype 2 receptor antagonist.

The present invention still further relates to the combination of acompound of the invention with antagonists of the histamine type 4receptor.

The present invention still further relates to the combination of acompound of the invention together with an alpha-1/alpha-2 adrenoceptoragonist vasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride,and ethylnorepinephrine hydrochloride.

The present invention still further relates to the combination of acompound of the invention together with anticholinergic agents includingmuscarinic receptor (M1, M2, and M3) antagonists such as atropine,hyoscine, glycpyrrrolate, ipratropium bromide; tiotropium bromide;oxitropium bromide; pirenzepine; and telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a beta-adrenoceptor agonist(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,and pirbuterol.

The present invention still further relates to the combination of acompound of the invention together with a chromone, including sodiumcromoglycate and nedocromil sodium.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention together with an inhaled glucocorticoid, suchas flunisolide, triamcinolone acetonide, beclomethasone dipropionate,budesonide, fluticasone propionate, ciclesonide, and mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (−11) and MMP-9 andMMP-12.

The present invention still further relates to the combination of acompound of the invention together with modulators of chemokine receptorfunction such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family);CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1for the C—X₃—C family.

The present invention still further relates to the combination of acompound of the invention together with a cytokine or modulator ofcytokine function, including alpha-, beta-, and gamma-interferon;interleukins (IL) including IL1 to 15, and interleukin antagonists orinhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of acompound of the invention together with an immunoglobulin (Ig) or Igpreparation or an antagonist or antibody modulating Ig function such asanti-IgE (omalizumab).

The present invention still further relates to the combination of acompound of the invention together with other systemic ortopically-applied anti-inflammatory agents including thalidomide andderivatives, retinoids, dithranol, and calcipotriol.

The present invention still further relates to the combination of acompound of the invention together with an antibacterial agent includingpenicillin derivatives, tetracyclines, macrolides, beta-lactams,flouroquinolones, and inhaled aminoglycosides; and antiviral agentsincluding acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir;amantadine, rimantadine; ribavirin; zanamavir and oseltamavir; proteaseinhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir;nucleoside reverse transcriptase inhibitors such as didanosine,lamivudine, stavudine, zalcitabine, zidovudine; non-nucleoside reversetranscriptase inhibitors such as nevirapine, efavirenz.

The present invention still further relates to the combination of acompound of the invention together with cardiovascular agents such ascalcium channel blockers, beta-adrenoceptor blockers,angiotensin-converting enzyme (ACE) inhibitors, angiotensin-2 receptorantagonists; lipid lowering agents such as statins, and fibrates;modulators of blood cell morphology such as pentoxyfylline;thrombolytics, and anticoagulants including platelet aggregationinhibitors.

The present invention still further relates to the combination of acompound of the invention together with CNS agents such asantidepressants (such as sertraline), anti-Parkinsonian drugs (such asdeprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine andrasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopaminereuptake inhibitors, NMDA antagonists, nicotine agonists, dopamineagonists and inhibitors of neuronal nitric oxide synthase), andanti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors,propentofylline or metrifonate.

The present invention still further relates to the combination of acompound of the invention together with agents for the treatment ofacute and chronic pain, including centrally and peripherally-actinganalgesics such as opioid analogues and derivatives, carbamazepine,phenytoin, sodium valproate, amitryptiline and other antidepressantagents, and non-steroidal anti-inflammatory agents.

The present invention still further relates to the combination of acompound of the invention together with parenterally ortopically-applied local anaesthetic agents such as lignocaine.

The present invention still further relates to the combination of acompound of the invention together with (i) tryptase inhibitors; (ii)platelet activating factor (PAF) antagonists; (iii) interleukinconverting enzyme (ICE) inhibitors; (iv) DH inhibitors; (v) adhesionmolecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii)MAP kinase inhibitors; (viii) glucose-6 phosphate dehydrogenaseinhibitors; (ix) kinin-B.sub1.- and B.sub2.-receptor antagonists; (x)anti-gout agents, e.g., colchicine; (xi) xanthine oxidase-inhibitors,e.g., allopurinol; (xii) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (xiii) growth hormone secretagogues;(xiv) transforming growth factor (TGFβ); (xv) platelet-derived growthfactor (PDGF); (xvi) fibroblast growth factor, e.g., basic fibroblastgrowth factor (bFGF); (xvii) granulocyte macrophage colony stimulatingfactor (GM-CSF); (xviii) capsaicin cream; (xix) Tachykinin NK.sub1. andNK.sub3. receptor antagonists selected from the group consisting ofNKP-60SC; SB-233412 (talnetant); and D-4418; (xx) elastase inhibitorsselected from the group consisting of UT-77 and ZD-0892; (xxi) TNF□converting enzyme inhibitors (TACE); (xxii) induced nitric oxidesynthase inhibitors (iNOS) or (xxiii) chemoattractantreceptor-homologous molecule expressed on TH2 cells, (CRTH2 antagonists)(xxiv) inhibitors of P38

The compounds of the present invention may also be used in combinationwith anti-osteoporosis agents including hormonal agents such asraloxifene, and biphosphonates such as alendronate.

The compounds of the invention may also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAIDs) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics, and intra-articulartherapies such as corticosteroids and hyaluronic acid derivatives, andnutritional supplements such as glucosamine.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of cancer. Suitable agentsto be used in combination include:

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine and paclitaxel; antitumour antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere); and topoisomerase inhibitors (for example epipodophyllotoxinslike etoposide and teniposide, amsacrine, topotecan and camptothecins);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) Agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab and the anti-erbb1 antibodycetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinaseinhibitors and serine/threonine kinase inhibitors, for exampleinhibitors of the epidermal growth factor family (for example EGFRfamily tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab, compounds such asthose disclosed in International Patent Applications WO 97/22596, WO97/30035, WO 97/32856 and WO 98/13354) and compounds that work by othermechanisms (for example linomide, inhibitors of integrin Δvβ3 functionand angiostatin);

(vi) vascular damaging agents such as combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO00/40529,WO 00/41669, WO01/92224, WO02/04434 and WO02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for the treatment of human diseases or conditions in whichmodulation of CRTh2 receptor activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention still further provides a method of treating diseasesmediated by PGD2 or its metabolites wherein the prostanoid binds to itsreceptor (especially CRTh2) receptor, which comprises administering to apatient a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt, solvate or prodrug thereof, ashereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compound of formula (I), prodrugs and pharmaceutically acceptablesalts and solvates thereof may be used on their own but will generallybe administered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as herein before defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Preferably the compound of the invention isadministered orally.

The invention will now be illustrated by the following examples inwhich, unless stated otherwise:

(i) when given, ¹H NMR data is quoted in the form of delta values formajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard;

(ii) mass spectra (MS): generally only ions which indicate the parentmass are reported, and unless otherwise stated the mass ion quoted isthe positive mass ion—(M+H)⁺;

(iii) the title compounds of the examples and methods were named usingthe ACD/name and ACD/name batch (version 6.0) from Advanced ChemicalDevelopment Inc, Canada;

(iv) unless stated otherwise, reverse phase HPLC was conducted using aSymmetry, NovaPak or Ex-Terra reverse phase silica column;

(v) solvents were dried with MgSO₄ or Na₂SO₄

(vi) the following abbreviations are used:

-   -   EtOAc Ethylacetate    -   DCM Dichloromethane    -   NMP N-methylpyrrolidine    -   DMF N,N-dimethylformamide    -   THF tetrahydrofuran    -   mcpba 3-chloroperoxybenzoic acid (Aldrich 77% max)    -   Pd(dppf)Cl₂        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),        complex with dichloromethane    -   RT room temperature

EXAMPLE 1 [(5-Methylbiphenyl-2-yl)oxy]acetic acid

(i) tert-Butyl(2-bromo-4-nitrophenoxy)acetate

tert-Butyl bromoacetate (3.06 ml) was added to a stirred mixture of2-bromo-4-nitrophenol (4 g) and potassium carbonate (2.62 g) in DMF (40ml) at RT. After 18 h the reaction was partitioned between diethyletherand water, the organics separated, dried and evaporated under reducedpressure. The residue was triturated with iso-hexane and filtered. Yield5.6 g

¹H NMR CDCl₃: δ 8.49 (1H, d); 8.21-8.16 (1H, m); 6.82 (1H, d); 4.71 (2H,s); 1.49 (9H, s)

(ii) tert-Butyl [(5-nitrobiphenyl-2-yl)oxy]acetate

A mixture of the product from step (i) (5.6 g), benzeneboronic acid(2.04 g), cesium fluoride (5.1 g) and Pd(dppf)Cl₂ (0.6 g) in dioxane (60ml) was heated under reflux for 4 h. After cooling the mixture waspartitioned between diethylether and water. The organics were separated,dried and evaporated under reduced pressure.

MS: APCI (+ve): 272 (M+1-^(t)Bu)

(iii) tert-Butyl [(5-aminobiphenyl-2-yl)oxy]acetate

Iron powder (5 g) was added to a solution of the product from step (ii)in acetic acid (100 ml) and stirred at RT for 16 h. The mixture wasfiltered through celite and evaporated under reduced pressure. Theresulting oil was made basic with aqueous sodium hydroxide solution thenextracted with EtOAc. The organics were dried, evaporated under reducedpressure and the residue purified by chromatography on silica elutingwith 8:1 DCM/EtOAc. Yield 3.74 g

MS: APCI (−ve): 272 (M−1-^(t)Bu)

(iv) tert-Butyl [(5-bromobiphenyl-2-yl)oxy]acetate

Copper (II) bromide (2.67 g) was added to a mixture of the product fromstep (iii) (3 g) and isoamylnitrite (2 ml) in acetonitrile (40 ml) andheated at 65° C. for 2 h. The solvent was evaporated under reducedpressure and the residue purified by chromatography on silica elutingwith 5:1 isohexane/diethylether. Yield 2.33 g

MS: APCI (−ve): 306/7 (M−1-^(t)Bu)

(v) tert-Butyl [(5-methylbiphenyl-2-yl)oxy]acetate

A mixture of the product from step (iv) (0.5 g), methylzinc chloride(3.44 ml, 2M in THF) and Pd(dppf)Cl₂ (0.1 g) in THF (10 ml) was heatedat 90° C. for 4 h. After cooling the mixture was partitioned betweendiethylether and water, the organics separated, dried and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica eluting with 4:1 isohexane/diethylether. Yield 0.43 g

MS: APCI (−ve): 241 (M−1-^(t)Bu)

(vi) [(5-Methylbiphenyl-2-yl)oxy]acetic acid

A solution of the product from step (v) (0.43 g) and trifluoroaceticacid (10 ml) in DCM (10 ml) was stirred at RT for 1 h then evaporatedunder reduced pressure. The residue was purified by chromatography onsilica eluting with 1:1 DCM/EtOAc+1% AcOH then by RPHPLC. Yield 0.03 g

¹H NMR DMSO-d6: δ 7.56-6.85 (8H, m); 4.64 (2H, s); 2.27 (3H, s)

MS: APCI (−ve): 241 (M−1)

EXAMPLE 2 {[5-Ethyl-4′-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid

(i) tert-Butyl(4-ethyl-2-iodophenoxy)acetate

Sodium iodide (4.41 g) then chloramine-T (8.29 g) was added to a stirredsolution of 4-ethylphenol (3 g) at 0° C. then allowed to warm to RT.After 1 h the mixture was diluted with 2M hydrochloric acid andextracted with diethylether. The organic layer was washed with aqueoussodium thiosulphate solution, dried and evaporated under reducedpressure. The residue was dissolved in DMF (30 ml) then tert-butylbromoacetate (3.9 ml) and potassium carbonate (3.31 g) added and stirredat RT overnight. The mixture was partitioned between water anddiethylether, the organics dried and evaporated under reduced pressure.The residue was purified by chromatography on silica eluting with 20%diethylether/isohexane. Yield 8.6 g

MS: APCI (−ve): 305 (M−1-^(t)Bu)

(ii) tert-Butyl {[5-ethyl-4′-(methylthio)biphenyl-2-yl]oxy}acetate

The subtitle compound was prepared by the method of example 1 step (ii)using the product from step (i) and 4-(methylthio)benzeneboronic acid.Yield 1.2 g

MS: APCI (−ve): 301 (M−1-^(t)Bu)

(iii) {[5-Ethyl-4′-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid

Mcpba (1.44 g) was added to a stirred solution of the product from step(ii) (1.2 g) in DCM (10 ml) at RT. After 16 h, the mixture waspartitioned between DCM and aqueous sodium metabisulphite solution, theorganics separated, washed with aqueous sodium hydrogencarbonatesolution, water, dried and evaporated under reduced pressure. Theresidue was dissolved in trifluoroacetic acid (10 ml) and DCM (10 ml),stirred at RT for 2 h then evaporated under reduced pressure. Theresidue was purified by RPHPLC. Yield 0.035 g

¹H NMR DMSO-d6: δ 7.95-6.94 (7H, m); 4.71 (2H, s); 3.25 (3H, s);2.62-2.57 (2H, q); 1.20-1.17 (3H, t)

MS: APCI (−ve): 333 (M−1)

EXAMPLE 3 {[4′-(Ethylsulfonyl)-5-methoxybiphenyl-2-yl]oxy}acetic acid

(i) tert-Butyl(2-bromo-4-methoxyphenoxy)acetate

The subtitle compound was prepared by the method of example 1 step (i)using 2-bromo-4-methoxyphenol. Yield 1.9 g

MS: APCI (−ve): 251 (M−1-^(t)Bu)

(ii) tert-Butyl {[4′-(ethylthio)-5-methoxybiphenyl-2-yl]oxy}acetate

The subtitle compound was prepared by the method of example 1 step (ii)using the product from step (i) and 4-(ethylthio)benzeneboronic acid.Yield 1.15 g

MS: APCI (−ve): 317 (M−1-^(t)Bu)

(iii) {[4′-(Ethylsulfonyl)-5-methoxybiphenyl-2-yl]oxy}acetic acid

The title compound was prepared by the method of example 2 step (iii)using the product from step (ii). Yield 0.12 g

¹H NMR DMSO-d6: δ 7.92-7.85 (4H, m); 7.01-6.92 (3H, m); 4.68-4.66 (2H,s); 3.76 (3H, s); 3.37-3.29 (2H, m); 1.17-1.12 (3H, t)

MS: APCI (−ve): 349 (M−1)

EXAMPLE 4[[4-Chloro-4′-(ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl)-2-yl]oxy]-aceticacid

(i) (2-Bromo-5-chloro-4-methylphenoxy)-acetic acid, 1,1-dimethylethylester

The subtitle compound was prepared by the method of example 1 step (i)using 6-bromo-4-chloro-m-cresol. Yield 0.8 g

¹H NMR CDCl₃: δ 7.52 (1H, s); 6.65 (1H, s); 4.60 (2H, s); 2.30 (3H, s);1.46 (9H, s)

(ii) 4-Bromo-3-methylphenyl ethyl sulfide

Bromine (2.2 ml) was added to a solution of1-(ethylthio)-3-methylbenzene (6.6 g) in acetic acid (20 ml) at 0° C.The mixture was stirred at RT for 2 h then the solvent removed underreduced pressure. The residue was purified by chromatography on silicaeluting with DCM. Yield 6.6 g

MS: APCI (+ve): 247/9 (M+1)

(iii) [4-(Ethylthio)-2-methylphenyl]-boronic acid

A 100 ml portion of a solution of the product from step (ii) (120.7 g)in THF (500 ml) was added to a stirred mixture of magnesium turnings(13.4 g) in THF (100 m]). Dibromoethane (0.2 ml) was added, and themixture gently refluxed on initiation. The remaining bromide solutionwas added dropwise maintaining the reaction at reflux. After additionthe mixture was allowed to cool to RT then cannulated into a stirredsolution of trimethylborate (112 ml) in THF (200 ml) at 0° C. Themixture was warmed to RT, stirred for 2 h then quenched with 2Mhydrochloric acid (300 ml). After stirring at RT for 18 h the THF wasremoved under reduced pressure and the mixture extracted withdiethylether. The organics were separated, washed with water, dried andevaporated under reduced pressure. The residue was triturated withdiethylether/isohexane and filtered. Yield 53.02 g

¹H NMR CDCl₃: δ 8.08 (1H, d); 7.18 (1H, d); 7.15 (1H, s); 3.04 (2H, q);2.76 (3H, s); 1.38 (3H, t)

(iv)[[4-Chloro-4′-(ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-aceticacid

A mixture of the product from step (i) (0.38 g), product from step (iii)(0.32 g), cesium fluoride (0.35 g) and Pd(dppf)Cl₂ (0.12 g) in dioxane(5 ml) was heated at 90° C. for 24 h. The solvent was evaporated underreduced pressure and the residue passed through a plug of silica elutingwith isohexane then 10% ethylacetate/isohexane. The resulting oil wasdissolved in DCM (10 ml) then trifluoroacetic acid (3 ml) added and themixture stirred for 1 h at RT the evaporated under reduced pressure. Theresidue was dissolved in water (10 ml) and acetonitrile (10 ml) thenoxone (2.5 g) added and stirred at RT. After 2 h the acetonitrile wasremoved under reduced pressure and the mixture extracted withethylacetate. The organic layer was extracted with aqueous sodiumhydroxide solution, then the aqeous layer acidified with 2M hydrochloricacid and extracted with ethylacetate. The last ethylacetate extractswere dried and evaporated under reduced pressure. The residue waspurified by RPHPLC eluting with acetonitrile/aqueous trifluoroaceticacid.

Yield 0.023 g

¹H NMR CDCl₃: δ 8.01 (1H, s); 7.77 (1H, d); 7.42 (1H, d); 7.18 (1H, s);7.00 (1H, s); 3.35 (2H, q); 2.50 (3H, s); 2.24 (3H, s); 1.13 (3H, t)

MS: ESI (−ve): 381 (M−1)

EXAMPLE 5[[4′-(Ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-acetic acid

The title compound was prepared by the method of example 4, yield 0.066g.

¹H NMR CDCl₃: δ 7.76 (1H, s); 7.71 (1H, dd); 7.41 (1H, d); 7.20 (1H,dd); 6.96 (1H, s); 6.84 (1H, d); 4.60 (2H, s); 3.30 (2H, q); 2.27 (3H,s); 2.06 (3H, s); 1.12 (3H, t)

MS: APCI (−ve): 347 (M−1)

EXAMPLE 6 2-[[3′-Cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoicacid

i) 5-Methyl-2-methoxyphenylboronic acid

The subtitle compound was prepared by the method of example 4 step (iii)using 4-methyl-2-bromoanisole (7.0 ml). Yield 2.6 g

¹H NMR DMSO: δ 7.64 (2H, s); 7.38 (1H, s); 7.18 (1H, d); 6.86 (1H, d);3.77 (3H, s); 2.22 (3H, s)

ii) 2′-Methoxy-5′-methyl-[1,1′-biphenyl]-3-carbonitrile

A mixture of the product from step (i) (0.8 g), 3-bromobenzonitrile(0.877 g), 2M aqueous sodium carbonate (3.0 ml) andtetrakistriphenylphosphine palladium (0) (0.2 g) in toluene (12 ml) andethanol (3 ml) was heated at reflux for 48 h. The mixture waspartitioned between EtOAc and water, the organics separated, dried, andevaporated under reduced pressure. The residue was purified bychromatography on silica eluting with 10% EtOAc/isohexane. Yield 0.92 g

¹H NMR DMSO: δ 7.9 (1H, d); 7.8 (2H, m); 7.61 (1H, t); 7.16-7.22 (2H,m); 7.04 (1H, d); 3.75 (3H, s); 2.29 (3H, s)

iii) 2′-Hydroxy-5′-methyl-[1,1′-biphenyl]-3-carbonitrile

A solution of boron tribromide (1M in DCM) (8 ml) was added to asolution of the product from step (ii) (0.92 g) in DCM (20 ml) at 0° C.and stirred for 2 h at 0° C. and at RT for 20 h. The reaction wasquenched with ice, extracted with DCM, washed with brine, dried (MgSO₄)and evaporated to give the subtitle compound. Yield 0.77 g

¹H NMR DMSO: δ 9.52 (1H, s); 7.95 (1H, d); 7.89 (1H, dt); 7.75 (1H, dt);7.6 (1H, t); 7.14 (1H, d); 7.02 (1H, dd); 6.86 (1H, d); 2.25 (3H, s)

iv) 2-[[3′-Cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid,1,1-dimethylethyl ester

Diethyl azodicarboxylate (0.3 ml) was added to a stirred solution of theproduct from step (iii) (0.3 g), tert-butyl-R-lactate (0.21 g) andtriphenylphosphine (0.375 g) in THF (10 ml) at 0° C. Stirred for 2 h,absorbed onto silica and purified by chromatography on silica elutingwith 10% EtOAc/isohexane to give the subtitle compound. Yield 0.386 g

¹H NMR DMSO: δ 8.04 (1H, s); 7.95 (1H, d); 7.78 (1H, d); 7.63 (1H, t);7.22 (1H, d); 7.15 (1H, dd); 6.86 (1H, d); 4.84 (1H, q); 2.28 (3H, s);1.39 (3H, d); 1.38 (9H, s)

v) 2-[[3′-Cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoic acid

The title compound was prepared by the method of example 1 step (vi)using the product from step (iv). Yield 0.075 g

¹H NMR DMSO: δ 8.23 (1H, t); 8.06 (1H, dt); 7.75 (1H, dt); 7.6 (1H, t);7.17 (1H, d); 7.08 (1H, dd); 6.85 (1H, d); 4.61 (1H, q); 2.27 (3H, s);1.35 (3H, d)

MS: APCI (−ve): 280

EXAMPLE 72-[[2′-Fluoro-5′-cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoicacid

The title compound was prepared by the method of example 4, using3-bromo-4-fluorobenzonitrile.

¹H NMR DMSO: δ 8.21 (1H, dd); 7.89 (1H, ddd); 7.5 (1H, t); 7.09-7.16(2H, m); 6.86 (1H, d); 4.58 (1H, q); 2.27 (3H, s); 1.3 (3H, d)

MS: APCI (−ve): 298

Pharmacological Data

Ligand Binding Assay

[³H]PGD₂ was purchased from Perkin Elmer Life Sciences with a specificactivity of 100-210 Ci/mmol. All other chemicals were of analyticalgrade.

HEK cells expressing rhCRTh2/Gα16 were routinely maintained in DMEMcontaining 10% Foetal Bovine Serum (HyClone), 1 mg/ml geneticin, 2 mML-glutamine and 1% non-essential amino acids. For the preparation ofmembranes, the adherent transfected HEKcells were grown to confluence intwo layer tissue culture factories (Fisher, catalogue numberTKT-170-070E). Maximal levels of receptor expression were induced byaddition of 500 mM sodium butyrate for the last 18 hours of culture. Theadherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell factory) and detached by the addition of 50 ml per cellfactory of ice-cold membrane homogenisation buffer [20 mM HEPES (H 7.4),0.1 mM dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonylfluoride and 100 μg/ml bacitracin]. Cells were pelleted bycentrifugation at 220×g for 10 minutes at 4° C., re-suspended in halfthe original volume of fresh membrane homogenisation buffer anddisrupted using a Polytron homogeniser for 2×20 second bursts keepingthe tube in ice at all times. Unbroken cells were removed bycentrifugation at 220×g for 10 minutes at 4° C. and the membranefraction pelleted by centrifugation at 90000×g for 30 minutes at 4° C.The final pellet was re-suspended in 4 ml of membrane homogenisationbuffer per cell factory used and the protein content determined.Membranes were stored at −80° C. in suitable aliquots.

All assays were performed in Corning clear bottomed, white 96-well NBSplates (Fisher). Prior to assay, the HEK cells membranes containingCRTh2 were coated onto SPA PVT WGA beads (Amersham). For coatingmembranes were incubated with beads at typically 25 μg membrane proteinper mg beads at 4° C. with constant agitation overnight. (The optimumcoating concentrations were determined for each batch of membranes) Thebeads were pelleted by centrifugation (800×g for 7 minutes at 4° C.),washed once with assay buffer (50 mM HEPES pH 7.4 containing 5 mMmagnesium chloride) and finally re-suspended in assay buffer at a beadconcentration of 10 mg/ml.

Each assay contained 20 μl of 6.25 nM [³H]PGD₂, 20 μl membrane saturatedSPA beads both in assay buffer and 10 μl of compound solution or13,14-dihydro-15-keto prostaglandin D₂ (DK-PGD₂, for determination ofnon-specific binding, Cayman chemical company). Compounds and DK-PGD₂were dissolved in DMSO and diluted in the same solvent to 100× therequired final concentration. Assay buffer was added to give a finalconcentration of 10% DMSO (compounds were now at 10× the required finalconcentration) and this was the solution added to the assay plate. Theassay plate was incubated at room temperature for 2 hours and counted ona Wallac Microbeta liquid scintillation counter (1 minute per well).

Compounds of formula (I) have an IC₅₀ value of less than (<) 10 μM.

Specifically, example 2 has a pIC₅₀=7.1 and example 3 has a pIC₅₀=6.6.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

in which: X is C₁₋₆alkyl or OR⁶; Y is selected from hydrogen, halogen,CN, nitro, SO₂R³, OR⁴, SR⁴, SOR³, SO₂NR⁴R⁵, CONR⁴R⁵, NR⁴R⁵, NR⁶SO₂R³,NR⁶CO₂R⁶, NR⁶COR³, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl orC₁₋₆alkyl, the latter four groups being optionally substituted by one ormore substituents independently selected from halogen, OR⁶ and NR⁶R⁷,S(O)_(n)R⁶; n is 0, 1 or 2; Z is aryl or a ring A, where A is a sixmembered heterocyclic aromatic ring containing one or more nitrogenatoms or may be a 6, 6 or 6,5 fused bicycle containing one or more O, N,S atoms, the aryl or A rings all being optionally substituted by one ormore substituents independently selected from from hydrogen, halogen,CN, OH, SH, nitro, COR⁹, CO₂R⁶, SO₂R⁹, OR⁹, SR⁹, SOR⁹, SO₂NR¹⁰R¹¹,CONR¹⁰R¹¹, NR¹⁰R¹¹, NHSO₂R⁹, NR⁹SO₂R⁹, NR⁶CO₂R⁶, NHCOR⁹, NR⁹COR⁹,NR⁶CONR⁴R⁵, NR⁶SO₂NR⁴R⁵, aryl, heteroaryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₇ cycloalkyl or C₁₋₆alkyl, the latter four groups being optionallysubstituted by one or more substituents independently selected fromhalogen, C₃-C₇ cycloalkyl, OR⁶, NR⁶R⁷, S(O)_(n)R⁶, CONR⁶R⁷, NR⁶COR⁷,SO₂NR⁶R⁷ and NR⁶SO₂R⁷. R¹ and R² independently represent a hydrogenatom, halogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl or aC₁₋₆alkyl group, the latter four groups being optionally substituted byone or more substituents independently selected from halogen, C₃-C₇cycloalkyl, NR⁶R⁷, OR⁶, S(O)_(n)R⁶; or R¹ and R² together can form a 3-8membered ring optionally containing one or more atoms selected from O,S, NR⁶ and itself optionally substituted by one or more C₁-C₃ alkyl orhalogen; R³ represents C₃-C₇ cycloalkyl or C₁₋₆alkyl which may beoptionally substituted by one or more substituents independentlyselected from halogen, C₃-C₇ cycloalkyl, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶,CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R and NR⁶SO₂R⁷; R⁴ and R⁵ independentlyrepresent hydrogen, C₃-C₇ cycloalkyl or C₁₋₆alkyl, the latter two groupsbeing optionally substituted by one or more substituents independentlyselected from halogen, C₃-C₇ cycloalkyl, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶,CONR⁶R⁷, NR⁶COR⁷⁵SO₂ NR⁶R⁷ and NR⁶SO₂R⁷; or R⁴ and R⁵ together with thenitrogen atom to which they are attached can form a 3-8 memberedsaturated heterocylic ring optionally containing one or more atomsselected from O, S(O)_(n), NR⁸, and itself optionally substituted byhalogen or C₁₋₃ alkyl; R⁶ and R⁷ independently represents a hydrogenatom or C₁-C₆ alkyl; R⁸ is hydrogen, C₁₋₄ alkyl, —COC₁-C₄ alkyl,CO₂C₁-C₄alkyl or CONR⁶C₁-C₄alkyl; R⁹ represents aryl, heteroaryl, C₃-C₇cycloalkyl or C₁₋₆alkyl, the latter two groups may be optionallysubstituted by one or more substituents independently selected fromhalogen, C₃-C₇ cycloalkyl, aryl, heteroaryl OR⁶ and NR⁶R⁷, S(O)_(n)R⁶,CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷ and NR⁶SO₂R⁷; R¹⁰ and R¹¹ independentlyrepresent aryl or heteroaryl, hydrogen, C₃-C₇ cycloalkyl or C₁₋₆alkyl,the latter two groups being optionally substituted by one or moresubstituents independently selected from halogen, C₃-C₇ cycloalkyl,aryl, heteroaryl, OR⁶ and NR⁶R⁷, S(O)_(n)R⁶, CONR⁶R⁷, NR⁶COR⁷, SO₂NR⁶R⁷and NR⁶SO₂R⁷; or R¹⁰ and R¹¹ together with the nitrogen atom to whichthey are attached can form a 3-8 membered saturated heterocylic ringoptionally containing one or more atoms selected from O, S(O)_(n), NR⁸,and itself optionally substituted by halogen or C₁-C₃ alkyl.
 2. Acompound according to claim 1 in which R¹ and R² independently representa hydrogen atom, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl or aC₁₋₆alkyl group, the latter four groups being optionally substituted byone or more substituents independently selected from halogen, C₃-C₇cycloalkyl, NR⁶R⁷, OR⁶, S(O)_(n)R⁶ or R¹ and R² together can form a 3-8membered ring optionally containing one or more atoms selected from O,S, NR⁶ and itself optionally substituted by one or more C₁-C₃ alkyl orhalogen;
 3. A compound according to claim 1 in which X is C₁₋₄alkyl orC₁₋₄alkoxy.
 4. A compound according to claim 1 in which Y is hydrogen.5. A compound according to claim 1 in which Z is phenyl or optionallysubstituted as defined in claim
 1. 6. A compound according to claim 1 inwhich Z is phenyl or optionally substituted by one or more substituentsindependently selected from halogen, C₁₋₃alkyl, cyano and SO₂R⁹.
 7. Acompound according to claim 1 in which R¹ and R² are both hydrogen orone is hydrogen and the other is C₁₋₃ alkyl.
 8. A compound according toclaim 1 selected from: [(5-Methylbiphenyl-2-yl)oxy]acetic acid,{[5-Ethyl-4′-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid,{[4′-(Ethylsulfonyl)-5-methoxybiphenyl-2-yl]oxy}acetic acid,[[4-Chloro-4′-(ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-aceticacid, [[4′-(Ethylsulfonyl)-2′,5-dimethyl[1,1′-biphenyl]-2-yl]oxy]-aceticacid, 2-[[3′-Cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoicacid,2-[[2′-Fluoro-5′-cyano-5-methyl[1,1′-biphenyl]-2-yl]oxy]-(2S)-propanoicacid, and pharmaceutically acceptable salts thereof.
 9. (canceled)
 10. Amethod of treating a disease mediated by prostaglandin D2, whichcomprises administering to a patient a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable salt asdefined in claim
 1. 11. A method of treating a respiratory disease in apatient suffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as defined in claim
 1. 12. The method of claim 11,wherein the respiratory disease is asthma or rhinitis.
 13. A compoundaccording to claim 2 in which X is C₁₋₄alkyl or C₁₋₄alkoxy.
 14. Acompound according to claim 2 in which Y is hydrogen.
 15. A compoundaccording to claim 2 in which Z is phenyl or optionally substituted asdefined in claim
 1. 16. A compound according to claim 2 in which Z isphenyl or optionally substituted by one or more substituentsindependently selected from halogen, C₁₋₃alkyl, cyano and SO₂R⁹.
 17. Acompound according to claim 2 in which R¹ and R² are both hydrogen orone is hydrogen and the other is C₁₋₃ alkyl.